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Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy

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ClinicalTrials.gov Identifier: NCT01679197
Recruitment Status : Completed
First Posted : September 5, 2012
Results First Posted : June 14, 2017
Last Update Posted : June 14, 2017
Information provided by (Responsible Party):

Study Description
Brief Summary:
This study involves research about an investigational medicine called metreleptin. The reason for this study is to find out how metreleptin can improve non-alcoholic steatohepatitis or nonalcoholic fatty liver disease associated with lipodystrophy, a rare disorder associated with abnormal loss of the body's fat tissue. In this study, metreleptin is considered to be investigational for the treatment of lipodystrophy. Metreleptin will be given via injections under the skin. We plan to continue therapy for a period of one year and evaluate the change in liver disease by a liver biopsy. We will also follow the metabolic parameters (e.g. blood cholesterol, liver function, insulin resistance) and body composition characteristics (e.g. the pattern of fat distribution in the body).

Condition or disease Intervention/treatment Phase
Fatty Liver Disease, Nonalcoholic Nonalcoholic Steatohepatitis Lipodystrophy Drug: Metreleptin Phase 2

Detailed Description:

The goal is to test the efficacy of restorative leptin therapy on the degree of hepatic steatosis and on amelioration of pathological features of NASH/NAFLD. In addition, the study will evaluate the impact of leptin therapy on total body insulin sensitivity and lipid levels as well as energy expenditure. In order to accomplish this aim, we now propose an efficacy study with recombinant human leptin therapy in patients with all forms of lipodystrophy who also have NASH/NAFLD.

  1. AIM 1: To determine the efficacy of leptin in promoting amelioration of body composition, hepatic steatosis and histopathological scores in patients with all forms of lipodystrophy and NAFLD/NASH. We will conduct a 1 year, open-label study, to assess the metabolic effects of recombinant human leptin (METRELEPTIN, AztraZeneca, Wilmington, DE). The primary outcome measure will be NASH scores. We will also explore body weight, insulin sensitivity, glucose and lipid control, body composition, and free fatty acid levels.
  2. AIM 2: To Investigate molecular effects of leptin therapy. In parallel to our preliminary studies, gene expression will be performed on individuals participating in Aim 1 at baseline and following 1 year of leptin. We will combine this with measures of liver metabolite levels to provide novel insights into alterations in metabolism that occur secondary to leptin therapy. We will also measure plasma metabolites at baseline and after 2 (optional), 24 and 48 weeks of therapy to assess the dynamic changes induced by leptin and correlate these changes with phenotypic measures.

Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Clinical Protocol to Investigate the Efficacy of Recombinant Human Leptin (Metreleptin) in Nonalcoholic Steatohepatitis (NASH) or Nonalcoholic Fatty Liver Disease (NAFLD) Associated With Lipodystrophy
Actual Study Start Date : October 8, 2012
Primary Completion Date : July 13, 2016
Study Completion Date : July 13, 2016

Arms and Interventions

Arm Intervention/treatment
Experimental: Treatment
Drug: Metreleptin
Other Name: (originally A100, recombinant-human-methionyl-leptin

Outcome Measures

Primary Outcome Measures :
  1. Liver Histopathology [ Time Frame: 1 year ]
    Primary outcome will be the total non-alcoholic steatohepatitis (NASH) score read histopathologically from the liver biopsy samples. This outcome measure quantifies the severity of fatty liver disease. At baseline and at the end of the year, patients have undergone a transcutaneous liver biopsy and the specimens were graded for the severity of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) pathology. Histological features of NAFLD/NASH were scored using the validated NASH-CRN (NASH Clinical Research Network) scoring system. This scoring system is the total of 4 subscales: steatosis (0-3), lobular inflammation (0-3), hepatocellular ballooning (0-2) and fibrosis (0-4), which are evaluated semi-quantitatively. The total scale range for this scoring system is 0-12, with 0 representing no features of fatty liver disease, and 12 representing the highest degree of fatty liver disease.

Secondary Outcome Measures :
  1. Liver Fat by MRI and MR Spectroscopy [ Time Frame: 1 year ]
    All enrolled patients will have a baseline MRI of the liver to evaluate liver volume and liver fat. For determination of hepatic fat content by MRI and MR spectroscopy in patients, a series of out-phase and in-phase MRI at multiple flip angles are used. By combination of out-phase and in-phase MRI at multiple flip-angles and TE times, relaxation-time effects can be removed to yield quantitative intra-hepatic (and other organs') fractional fat content throughout the liver in a few breath-hold intervals.

  2. Liver Function Tests [ Time Frame: 1 year ]
    AST and ALT are the liver function tests. We are reporting the liver function tests where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.

  3. Fasting Lipids [ Time Frame: 1 year ]
    Cholesterol, triglycerides, HDL cholesterol, and LDL together make up the lipid profile and must be reported together. We are reporting the lipid profile where the treatment group arm would normally be listed, though, we are looking at the same single arm population of 23 participants who received treatment in this study.

  4. Fasting Glucose [ Time Frame: 1 year ]
  5. Body Weight [ Time Frame: 1 year ]

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years and older   (Child, Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Is male or female ≥ 5 years old at baseline.
  • Is male, female not of childbearing potential, or meets all the following criteria if female of childbearing potential (including perimenopausal women who have had a menstrual period within one year):

    • Not breastfeeding
    • Negative pregnancy test result (human chorionic gonadotropin, beta subunit [βhCG]) at baseline (not applicable to hysterectomized females).
    • Must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate when use consistently and correctly, such as implants, injectables, oral contraceptives, some intrauterine contraceptive devices, sexual abstinence, tubal ligation, or a vasectomized partner) during the entire duration of metreleptin treatment.
  • Has physician-confirmed lipodystrophy as defined by evidence of generalized (whole body) or partial (limbs) loss of body fat outside the range of normal variation.
  • Alcohol consumption of less than 40 grams/week.
  • A liver ultrasound confirming non-alcoholic fatty liver disease, or previous liver biopsy confirming NASH status.
  • If ≥ 18 years of age, is able to read, understand and sign the U of M IRBMED approved informed consent form (ICF), communicate with study physician and study team, understand and comply with protocol requirements.
  • If < 18 and ≥ 7 years of age, is able to read, understand and sign the appropriate U of M IRBMED approved assent form and has a parent or legal guardian that is able to read, understand and sign the ICF.
  • If < 7 and ≥ 5 years of age or unable to read, the appropriate assent form must be explained to the child.
  • If previously treated with thiazolidinediones or Vitamin E, stable dose of these medications for at least 3 months.

Exclusion Criteria:

  • Presence of advanced liver disease (as evidenced by abnormal synthetic function, abnormal PT or albumin).
  • Evidence of other etiologies of viral hepatitis.
  • Presence of clinically significant hematologic abnormalities (such as neutropenia and/or lymphadenopathy).
  • Presence of HIV infection.
  • Very poorly controlled diabetes; HbA1c >10%
  • Inability to give informed consent.
  • Presence of ESRD, any type of active cancer, or >class 2 congestive heart failure ((New York Heart Association Functional Classification System), based on medical history and physical examination.
  • Active infection (may be transient).
  • Has known allergies to E. coli-derived proteins or hypersensitivity to any component of metreleptin treatment.
  • Any other condition in the opinion of the investigators that may impede successful data collection.
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01679197

United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
Sponsors and Collaborators
University of Michigan
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Principal Investigator: Elif A Oral, MD, MS University of Michigan
More Information

Responsible Party: Elif Oral, Associate Professor, University of Michigan
ClinicalTrials.gov Identifier: NCT01679197     History of Changes
Other Study ID Numbers: MCRU 2834
R01DK088114-02 ( U.S. NIH Grant/Contract )
First Posted: September 5, 2012    Key Record Dates
Results First Posted: June 14, 2017
Last Update Posted: June 14, 2017
Last Verified: May 2017

Keywords provided by Elif Oral, University of Michigan:
Nonalcoholic fatty liver disease
Nonalcoholic steatohepatitis
Diabetes mellitus

Additional relevant MeSH terms:
Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases
Skin Diseases, Metabolic
Skin Diseases
Lipid Metabolism Disorders
Metabolic Diseases